tbuckley/cabot-search huggingface dataset:
Genome-scale CRISPR–Cas9 screen reveals novel regulators of B7-H3 in tumor cells
Authors: Shasha Zhao, Yuelong Wang, Nian Yang, Min Mu, Zhiguo Wu, Hexian Li, Xin Tang, Kunhong Zhong, Zongliang Zhang, Cheng Huang, Ting Cao, Meijun Zheng, Guoqing Wang, Chunlai Nie, Hui Yang, Gang Guo, Liangxue Zhou, Xi Zheng, Aiping Tong
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Despite advances in B7 homolog 3 protein (B7-H3) based immunotherapy, the development of drug resistance remains a major clinical concern. The heterogeneity and emerging loss of B7-H3 expression are the main causes of drug resistance and treatment failure in targeted therapies, which reveals an urgent need to elucidate the mechanism underlying the regulation of B7-H3 expression. In this study, we identified and explored the crucial role of the transcription factor SPT20 homolog (SP20H) in B7-H3 expression and tumor progression. Methods Here, we performed CRISPR/Cas9-based genome scale loss-of-function screening to identify regulators of B7-H3 in human ovarian cancer cells. Signaling pathways altered by SP20H knockout were revealed by RNA sequencing. The regulatory role and mechanism of SP20H in B7-H3 expression were validated using loss-of-function and gain-of-function assays in vitro. The effects of inhibiting SP20H on tumor growth and efficacy of anti-B7-H3 treatment were evaluated in tumor-bearing mice. Results We identified SUPT20H (SP20H) as negative and eIF4E as positive regulators of B7-H3 expression in various cancer cells. Furthermore, we provided evidence that either SP20H loss or TNF-α stimulation in tumor cells constitutively activates p38 MAPK-eIF4E signaling, thereby upregulating B7-H3 expression. Loss of SP20H upregulated B7-H3 expression both in vitro and in vivo. Additionally, deletion of SP20H significantly suppressed tumor growth and increased immune cells infiltration in tumor microenvironment. More importantly, antibody–drug conjugates targeting B7-H3 exhibited superior antitumor performance against SP20H-deficient tumors relative to control groups. Conclusions Activation of p38 MAPK-eIF4E signaling serves as a key event in the transcription initiation and B7-H3 protein expression in tumor cells. Genetically targeting SP20H upregulates target antigen expression and sensitizes tumors to anti-B7-H3 treatment. Collectively, our findings provide new insight into the mechanisms underlying B7-H3 expression and introduce a potential synergistic target for existing antibody-based targeted therapy against B7-H3.
Immunity and infectivity in covid-19
Authors: Claire Johnston, Harriet Hughes, Sion Lingard, Stephen Hailey, Brendan Healy
Journal: BMJ (2022)

Mechanical insufflation-exsufflation (MI-E) is traditionally used in the neuromuscular population. There is growing interest of MI-E use in invasively ventilated critically ill adults. We aimed to map current evidence on MI-E use in invasively ventilated critically ill adults. Two authors independently searched electronic databases MEDLINE, Embase, and CINAHL via the Ovid platform; PROSPERO; Cochrane Library; ISI Web of Science; and International Clinical Trials Registry Platform between January 1990–April 2021. Inclusion criteria were (1) adult critically ill invasively ventilated subjects, (2) use of MI-E, (3) study design with original data, and (4) published from 1990 onward. Data were extracted by 2 authors independently using a bespoke extraction form. We used Mixed Methods Appraisal Tool to appraise risk of bias. Theoretical Domains Framework was used to interpret qualitative data. Of 3,090 citations identified, 28 citations were taken forward for data extraction. Main indications for MI-E use during invasive ventilation were presence of secretions and mucus plugging (13/28, 46%). Perceived contraindications related to use of high levels of positive pressure (18/28, 68%). Protocolized MI-E settings with a pressure of ±40 cm H<sub>2</sub>O were most commonly used, with detail on timing, flow, and frequency of prescription infrequently reported. Various outcomes were re-intubation rate, wet sputum weight, and pulmonary mechanics. Only 3 studies reported the occurrence of adverse events. From qualitative data, the main barrier to MI-E use in this subject group was lack of knowledge and skills. We concluded that there is little consistency in how MI-E is used and reported, and therefore, recommendations about best practices are not possible.
B cell receptor signaling drives APOBEC3 expression via direct enhancer regulation in chronic lymphocytic leukemia B cells
Authors: Zhiquan Wang, Huihuang Yan, Justin C. Boysen, Charla R. Secreto, Renee C. Tschumper, Dania Ali, Qianqian Guo, Jian Zhong, Jiaqi Zhou, Haiyun Gan, Chuanhe Yu, Diane F. Jelinek, Susan L. Slager, Sameer A. Parikh, Esteban Braggio, Neil E. Kay
Journal: Blood Cancer Journal (2022)

Constitutively activated B cell receptor (BCR) signaling is a primary biological feature of chronic lymphocytic leukemia (CLL). The biological events controlled by BCR signaling in CLL are not fully understood and need investigation. Here, by analysis of the chromatin states and gene expression profiles of CLL B cells from patients before and after Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib treatment, we show that BTKi treatment leads to a decreased expression of APOBEC3 family genes by regulating the activity of their enhancers. BTKi treatment reduces enrichment of enhancer marks (H3K4me1 and H3K27ac) and chromatin accessibility at putative APOBEC3 enhancers. CRISPR-Cas9 directed deletion or inhibition of the putative APOBEC3 enhancers leads to reduced APOBEC3 expression. We further find that transcription factor NFATc1 couples BCR signaling with the APOBEC3 enhancer activity to control APOBEC3 expression. We also find that enhancer-regulated APOBEC3 expression contributes to replication stress in malignant B cells. In total we demonstrate a novel mechanism for BTKi suppression of APOBEC3 expression via direct enhancer regulation in an NFATc1-dependent manner, implicating BCR signaling as a potential regulator of leukemic genomic instability.
Adverse SARS-CoV-2-associated outcomes among people experiencing social marginalisation and psychiatric vulnerability: A population-based cohort study among 4,4 million people
Authors: Sandra Feodor Nilsson, Thomas Munk Laursen, Merete Osler, Carsten Hjorthøj, Michael E. Benros, Steen Ethelberg, Kåre Mølbak, Merete Nordentoft
Journal: The Lancet Regional Health - Europe (2022)

Knowledge of the adverse problems related to SARS-CoV-2 infection in marginalised and deprived groups may help to prioritise more preventive efforts in these groups. We examined adverse outcomes associated with SARS-CoV-2 infection among vulnerable segments of society.Using health and administrative registers, a population-based cohort study of 4.4 million Danes aged at least 15 years from 27 February 2020 to 15 October 2021 was performed. People with 1) low educational level, 2) homelessness, 3) imprisonment, 4) substance abuse, 5) supported psychiatric housing, 6) psychiatric admission, and 7) severe mental illness were main exposure groups. Chronic medical conditions were included for comparison. COVID-19-related outcomes were: 1) hospitalisation, 2) intensive care, 3) 60-day mortality, and 4) overall mortality. PCR-confirmed SARS-CoV-2 infection and PCR-testing were also studied. Poisson regression analysis was used to compute adjusted incidence and mortality rate ratios (IRRs, MRRs).Using health and administrative registers, we performed a population-based cohort study of 4,412,382 individuals (mean age 48 years; 51% females). In all, 257,450 (5·8%) individuals had a PCR-confirmed SARS-CoV-2 infection. After adjustment for age, calendar time, and sex, we found that especially people experiencing homelessness had high risk of hospitalisation (IRR 4·36, 95% CI, 3·09-6·14), intensive care (IRR 3·12, 95% CI 1·29-7·52), and death (MRR 8·17, 95% CI, 3·66-18·25) compared with people without such experiences, but increased risk was found for all studied groups. Furthermore, after full adjustment, including for status of vaccination against SARS-CoV-2 infection, individuals with experiences of homelessness and a PCR-confirmed SARS-CoV-2 infection had 41-times (95% CI, 24·84-68·44) higher risk of all-cause death during the study period compared with individuals without. Supported psychiatric housing was linked to almost 3-times higher risk of hospitalisation and 60-day mortality following SARS-CoV-2 infection compared with the general population with other living circumstances.Socially marginalised and psychiatrically vulnerable individuals had substantially elevated risks of adverse health outcomes following SARS-CoV-2 infection. The results highlight that pandemic preparedness should address inequalities in health, including infection prevention and vaccination of vulnerable groups.Novo Nordisk Foundation.
Association of BNT162b2 Vaccine Third Dose Receipt With Incidence of SARS-CoV-2 Infection, COVID-19–Related Hospitalization, and Death Among Residents of Long-term Care Facilities, August to October 2021
Authors: Khitam Muhsen, Nimrod Maimon, Amiel Yaron Mizrahi, Baruch Varticovschi, Omri Bodenheimer, Dani Cohen, Ron Dagan
Journal: JAMA Network Open (2022)

COVID-19 vaccine might be less immunogenic and effective among residents of long-term care facilities (LTCFs).To examine the association of BNT162b2 third dose (first booster dose) with overall SARS-CoV-2 infection, COVID-19 hospitalizations, and mortality among LTCF residents during a nationwide surge of the Delta variant in Israel.This observational cohort study conducted nationwide COVID-19 surveillance in LTCFs in Israel between August and October 2021. Participants were residents of LTCFs aged 60 years or older.Vaccination with the third dose of BNT162b2 vaccine vs receipt of 2 doses at least 5 months earlier, based on self-preference and choice.The cumulative incidences of reverse transcription-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection, COVID-19 hospitalizations, and COVID-19-related deaths more than 7 days after vaccination with the third dose were compared between the groups using Kaplan-Meier curves. Hazard ratios (HRs) and 95% CIs were obtained using multivariable Cox regression models.Among 18 611 residents included in the analysis, 12 715 (68.3%) were female, 463 (2.5%) were from the Arab population, 16 976 (91.2%) were from the general Jewish population, and 618 (3.3%) were from the ultraorthodox Jewish population; the mean (SD) age was 81.1 (9.2) years; 16 082 residents received their first booster dose (third dose) and 2529 were vaccinated with 2 doses at least 5 months earlier. The median (IQR) follow-up durations were 66 (60-70) days among 3-dose recipients and 56 (53-62) days among 2-dose-only recipients; 107 residents had SARS-CoV-2 infection after 7 days following vaccination with the booster dose compared with 185 among the 2-dose only group (cumulative incidence: 0.7% vs 7.5%; adjusted HR, 0.11 [95% CI, 0.07-0.15]). The respective adjusted HRs were 0.07 (95% CI, 0.03-0.14) and 0.10 (95% CI, 0.04-0.24) for the associations of vaccination with the third dose with hospitalization for mild-to-moderate COVID-19 and severe illness. Five COVID-19-related deaths occurred among the third dose vaccinees during the follow-up period compared with 22 among the 2-dose-only vaccinees (cumulative rate: 0.04% vs 0.9%; adjusted HR, 0.04 [95% CI, 0.009-0.16]).This cohort study found significant inverse associations between vaccination with the third dose of the BNT162b2 vaccine with overall SARS-CoV-2 infection, COVID-19 hospitalizations, severe disease, and COVID-19-related deaths among LTCF residents during a massive surge caused by the Delta variant in Israel.
Error in Figure 2B
Journal: JAMA Network Open (2022)

Lina Lundström, MSc; Oskar Flygare, MSc; Erik Andersson, PhD; Jesper Enander, PhD; Matteo Bottai, PhD; Volen Z. Ivanov, PhD; Julia Boberg, MSc; Diana Pascal, MD, PhD; David Mataix-Cols, PhD; Christian Rück, MD, PhD
Laparoscopic management of isolated nodal recurrence in gynecological malignancies is safe and feasible even for large metastatic nodes up to 8 cm: A prospective case series
Authors: Elisabetta Sanna, Clelia Madeddu, Fabrizio Lavra, Sara Oppi, Mario Scartozzi, Pier Giorgio Calò, Antonio Macciò
Journal: International Journal of Surgery (2022)

The surgical treatment of isolated lymph node recurrence (ILNR) of gynecological malignancies is still debated. The feasibility and effectiveness of minimally invasive lymphadenectomy have been reported by few studies; however, it remains unclear what the upper tumor size limit is for a minimally invasive approach. We prospectively analyzed cases of ILNR treated by laparoscopy in our unit while focusing on the safety and feasibility of resecting large tumors suspected of recurrence using a minimally invasive approach.We carried out a prospective observational case-series study. We included all consecutive patients with ILNR from gynecological cancers who underwent minimally invasive lymphadenectomy at our unit from June 2013 to June 2021 to assess the safety and feasibility of such a surgical approach. We also evaluated the oncological outcome in terms of further recurrence, site of recurrence, and survival.Twenty-seven patients with ILNR due to gynecological malignancies were included (ovarian cancer, 12; uterine malignancies, 12; cervical cancer, 3). Three had remarkably large LNs up to 8 cm: these emblematic cases have been reported in detail with accompanying videos of the surgical procedure. The most frequent site of ILNR was aortic (67%). Recurrent LNs were completely resected in all cases; none of the procedures was converted to open surgery. The median follow-up duration was 24 months. Ten patients (37%) had a new recurrence. To date five patients (18.5%) have succumbed, four (14.8%) are alive with evidence of disease, and 18 (66.7%) are alive with no evidence of disease.Minimally invasive surgery for ILNR in gynecological malignancies may be an option feasible, safe, and effective in terms of oncological outcomes, even for large tumors. It also allows quicker recovery with early initiation of appropriate postoperative systemic chemotherapy, in the context of an optimal multimodal therapeutic approach.
KinasePhos 3.0: Redesign and Expansion of the Prediction on Kinase-Specific Phosphorylation Sites
Authors: Renfei Ma, Shangfu Li, Wenshuo Li, Lantian Yao, Hsien-Da Huang, Tzong-Yi Lee
Journal: Genomics Proteomics & Bioinformatics (2022)

The purpose of this work is to enhance KinasePhos, a machine learning-based kinase-specific phosphorylation site prediction tool. Experimentally verified kinase-specific phosphorylation data were collected from PhosphoSitePlus, UniProtKB, the GPS 5.0, and Phospho.ELM. In total, 41,421 experimentally verified kinase-specific phosphorylation sites were identified. A total of 1380 unique kinases were identified, including 753 with existing classification information from KinBase and the remaining 627 annotated by building a phylogenetic tree. Based on this kinase classification, a total of 771 predictive models were built at the individual, family, and group levels, using at least 15 experimentally verified substrate sites in positive training datasets. The improved models demonstrated their effectiveness compared with other prediction tools. For example, the prediction of sites phosphorylated by the protein kinase B, casein kinase 2, and protein kinase A families had accuracies of 94.5%, 92.5%, and 90.0%, respectively. The average prediction accuracy for all 771 models was 87.2%. For enhancing interpretability, the SHapley Additive exPlanations (SHAP) method was employed to assess feature importance. The web interface of KinasePhos 3.0 has been redesigned to provide comprehensive annotations of kinase-specific phosphorylation sites on multiple proteins. Additionally, considering the large scale of phosphoproteomic data, a downloadable prediction tool is available at https://awi.cuhk.edu.cn/KinasePhos/download.html or https://github.com/tom-209/KinasePhos-3.0-executable-file.
Organizational Perspectives on Technical Capabilities and Barriers Related to Pediatric Data Sharing and Confidentiality
Authors: Michael Bedgood, Cynthia L. Kuelbs, Veena G. Jones, Natalie Pageler
Journal: JAMA Network Open (2022)

This qualitative study describes results from a semistructured interview investigating technical capabilities and barriers related to pediatric data sharing and confidentiality that was administered to health care organizations participating in the California Pediatric Informatics Collaborative.
Monkeypox: What’s behind WHO’s decision not to declare a public health emergency?
Authors: Luke Taylor
Journal: BMJ (2022)

Monkeypox: What's behind WHO's decision not to declare a public health emergency?With cases rising globally, the decision not to classify the monkeypox outbreak as a public health emergency of international concern has raised eyebrows, as Luke Taylor reports Luke TaylorWorld Health Organization officials have said that the global spread of monkeypox does not yet merit declaring the outbreak a public health emergency of international concern (PHEIC). 1 The decision, announced on 25 June, was made after two days of deliberation following a WHO emergency committee.
Publisher Correction: A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex
Authors: Danny Antaki, James Guevara, Adam X. Maihofer, Marieke Klein, Madhusudan Gujral, Jakob Grove, Caitlin E. Carey, Oanh Hong, Maria J. Arranz, Amaia Hervas, Christina Corsello, Keith K. Vaux, Alysson R. Muotri, Lilia M. Iakoucheva, Eric Courchesne, Karen Pierce, Joseph G. Gleeson, Elise B. Robinson, Caroline M. Nievergelt, Jonathan Sebat
Journal: Nature Genetics (2022)
Acid–Base Homeostasis and Implications to the Phenotypic Behaviors of Cancer
Authors: Yi Zhou, Wennan Chang, Xiaoyu Lu, Jin Wang, Chi Zhang, Ying Xu
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Acid–base homeostasis is a fundamental property of living cells, and its persistent disruption in human cells can lead to a wide range of diseases. In this study, we conducted a computational modeling analysis of transcriptomic data of 4750 human tissue samples of 9 cancer types in The Cancer Genome Atlas (TCGA) database. Built on our previous study, we quantitatively estimated the average production rate of OH− by cytosolic Fenton reactions, which continuously disrupt the intracellular pH (pHi) homeostasis. Our predictions indicate that all or at least a subset of 43 reprogrammed metabolisms (RMs) are induced to produce net protons (H+) at comparable rates of Fenton reactions to keep the pHi stable. We then discovered that a number of well-known phenotypes of cancers, including increased growth rate, metastasis rate, and local immune cell composition, can be naturally explained in terms of the Fenton reaction level and the induced RMs. This study strongly suggests the possibility to have a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors. In addition, strong evidence is provided to demonstrate that a popular view that Na+/H+ exchangers along with lactic acid exporters and carbonic anhydrases are responsible for the intracellular alkalization and extracellular acidification in cancer may not be justified.
Initial outcomes of a community health worker programme for patients with type 2 diabetes in refugee camps at the West Bank, occupied Palestinian territory: a retrospective, matched cohort study
Authors: Asmaa Rimawi, Henry Louis, David Scales, Jawad Abu Kheiran, Nashat Jawabreh, Sofia Yunez, Masako Horino, Akihiro Seita, Bram Wispelwey
Journal: The Lancet (2022)
Monocyte-derived alveolar macrophages autonomously determine severe outcome of respiratory viral infection
Authors: Fengqi Li, Federica Piattini, Lea Pohlmeier, Qian Feng, Hubert Rehrauer, Manfred Kopf
Journal: Science Immunology (2022)

Various lung insults can result in replacement of resident alveolar macrophages (AM) by bone marrow monocyte–derived (BMo)–AM. However, the dynamics of this process and its long-term consequences for respiratory viral infections remain unclear. Using several mouse models and a marker to unambiguously track fetal monocyte–derived (FeMo)–AM and BMo-AM, we established the kinetics and extent of replenishment and their function to recurrent influenza A virus (IAV) infection. A massive loss of FeMo-AM resulted in rapid replenishment by self-renewal of survivors, followed by the generation of BMo-AM. BMo-AM progressively outcompeted FeMo-AM over several months, and this was due to their increased glycolytic and proliferative capacity. The presence of both naïve and experienced BMo-AM conferred severe pathology to IAV infection, which was associated with a proinflammatory phenotype. Furthermore, upon aging of naïve mice, FeMo-AM were gradually replaced by BMo-AM, which contributed to IAV disease severity in a cell-autonomous manner. Together, our results suggest that the origin rather than training of AM determines long-term function to respiratory viral infection and provide an explanation for the increased severity of infection seen in the elderly.
Effectiveness of BNT162b2 vaccine against SARS-CoV-2 infection and severe COVID-19 in children aged 5–11 years in Italy: a retrospective analysis of January–April, 2022
Authors: Chiara Sacco, Martina Del Manso, Alberto Mateo-Urdiales, Maria Cristina Rota, Daniele Petrone, Flavia Riccardo, Antonino Bella, Andrea Siddu, Serena Battilomo, Valeria Proietti, Patrizia Popoli, Francesca Menniti Ippolito, Anna Teresa Palamara, Silvio Brusaferro, Giovanni Rezza, Patrizio Pezzotti, Massimo Fabiani
Journal: The Lancet (2022)
COVID-19 vaccination antibody responses in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria
Authors: Alexandra Pike, Claire McKinley, Briony Forrest, Rebecca Scott, Emily Charlton, Emma Scott, Tapiwa Zhakata, Mark Harland, Deborah Clarke, John R Davies, Aurora Toogood, Nicola Houghton, Nora Youngs, Catherine Barnfield, Stephen Richards, Daniel Payne, Louise Arnold, Tahla Munir, Petra Muus, Morag Griffin, Richard J Kelly, Peter Hillmen, Darren Newton
Journal: The Lancet Haematology (2022)
Editor's Note: Nanoparticles Engineered with Rituximab and Loaded with Nutlin-3 Show Promising Therapeutic Activity in B-Leukemic Xenografts
Authors: Rebecca Voltan, Paola Secchiero, Barbara Ruozi, Flavio Forni, Chiara Agostinis, Lorenzo Caruso, Maria Angela Vandelli, Giorgio Zauli
Journal: Clinical Cancer Research (2022)

The editors are publishing this note to inform readers of a concern about this article (1): the tubulin control in Fig. 2A is similar to both the EHEB tubulin and the JVM2 tubulin panels in Fig. 2C of the authors’ earlier work (2).
The effectiveness of intensive home treatment as a substitute for hospital admission in acute psychiatric crisis resolution in the Netherlands: a two-centre Zelen double-consent randomised controlled trial
Authors: Jurgen Cornelis, Ansam Barakat, Matthijs Blankers, Jaap Peen, Nick Lommerse, Merijn Eikelenboom, Jeroen Zoeteman, Henricus Van, Aartjan T F Beekman, Jack Dekker
Journal: The Lancet Psychiatry (2022)